Project Summary Endothelial cells of the tumor vasculature play an important role in tumor progression, metastasis and resistance to therapies in breast cancer. Our lab has identified a group of seven microRNAs (miRs) that are upregulated during DNA damage and oxidative stress in endothelial cells. Some of these miRs induce DNA damage, cell death and senescence in endothelial cells in vitro and in vivo. We have characterized a DNA damage network as being targets of these miRs. This proposal aims to investigate A) How these miRs are regulated in response to stressors? B) What are the mechanisms by which these miR-target network interactions lead to endothelial dysfunction and finally C) evaluate a novel anti-angiogenic strategy by targeting this miR-target network and any potential synergy with VEGF inhibition in vivo. Our studies will establish a new paradigm for inhibiting angiogenesis using miR-mediated disruption of DNA repair.